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ABSTRACT: Recent evidence supports the notion that transformation of undifferentiated neural stem cell (NSC) precursors may contribute
to the development of glioblastoma multiforme (GBM). The over-expression and mutation of the epidermal growth factor receptor
(EGFR), along with other cellular pathway mutations, plays a significant role in GBM maintenance progression. Though EGFR
signaling is important in determining neural cell fate and conferring astrocyte differentiation, there is a limited understanding
of its role in NSC and tumor stem cell (TSC) biology. We hypothesized that EGFR expression and mutation in post-natal NSCs
may contribute to cellular aggressiveness including enhanced cellular proliferation, survival and migration. Stable subclones
of C17.2 murine NSCs were transfected to over-express either the wild-type EGFR (wtEGFR) or its most common mutated variant
EGFRvIII. Activated EGFR signaling in these cells induced behaviors characteristic of GBM TSCs, including enhanced proliferation,
survival and migration, even in the absence of EGF ligand. wtEGFR activation was also found to block neuronal differentiation
and was associated with a dramatic increase in chemotaxis in the presence of EGF. EGFRvIII expression lead to an increase
in NSC proliferation and survival, while it simultaneously blocked neuronal differentiation and promoted glial fate. Our findings
suggest that activated EGFR signaling enhances the aggressiveness of NSCs. Understanding the regulatory mechanisms of NSCs
may lend insight into deregulated mechanisms of GBM TSC invasion, proliferation, survival and resistance to current treatment
modalities.
KeywordsEGFR-Neural stem cells-Glioma-Brain tumors
Journal of Neuro-Oncology 04/2012; 97(3):323-337. · 3.21 Impact Factor
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Su Wang,
Devin Chandler-Militello,
Gang Lu, Neeta S Roy,
Alex Zielke,
Romane Auvergne,
Nancy Stanwood,
Daniel Geschwind,
Giovanni Coppola,
Silvia K Nicolis,
Fraser J Sim,
Steven A Goldman
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ABSTRACT: Sox2 is expressed by neural stem and progenitor cells, and a sox2 enhancer identifies these cells in the forebrains of both fetal and adult transgenic mouse reporters. We found that an adenovirus encoding EGFP placed under the regulatory control of a 0.4 kb sox2 core enhancer selectively identified multipotential and self-renewing neural progenitor cells in dissociates of human fetal forebrain. Upon EGFP-based fluorescence-activated cell sorting (FACS), the E/sox2:EGFP(+) isolates were propagable for up to 1 year in vitro, and remained multilineage competent throughout. E/sox2:EGFP(+) cells expressed more telomerase enzymatic activity than matched E/sox2:EGFP-depleted populations, and maintained their telomeric lengths with successive passage. Gene expression analysis of E/sox2:EGFP-sorted neural progenitor cells, normalized to the unsorted forebrain dissociates from which they derived, revealed marked overexpression of genes within the notch and wnt pathways, and identified multiple elements of each pathway that appear selective to human neural progenitors. Sox2 enhancer-based FACS thus permits the prospective identification and direct isolation of a telomerase-active population of neural stem cells from the human fetal forebrain, and the elucidation of both the transcriptome and dominant signaling pathways of these critically important cells.
Journal of Neuroscience 11/2010; 30(44):14635-48. · 7.11 Impact Factor
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ABSTRACT: The statins have been proposed as possible therapeutic agents for a variety of autoimmune disorders, including multiple sclerosis. In a genomic screen, we found that glial progenitor cells (GPCs) of the adult human white matter expressed significant levels of the principal statin target, HMG-CoA reductase, as well as additional downstream members of the sterol synthesis pathway. We therefore asked if statin treatment might influence the differentiated fate of adult glial progenitor cells. To assess the functional importance of the sterol synthesis pathway to adult human glial progenitors, we used simvastatin or pravastatin to inhibit HMG-CoA reductase, and then assessed the phenotypic differentiation of the progenitors, as well as the molecular concomitants thereof. We found that both statins induced a dose-dependent induction of oligodendrocyte phenotype, and concomitant reduction in progenitor number. Oligodendrocyte commitment was associated with induction of the sterol-regulated nuclear co-receptor PPARgamma, and could be blocked by the specific PPARgamma antagonist GW9662. Thus, statins may promote oligodendrocyte lineage commitment by parenchymal glial progenitor cells; this might reduce the available progenitor pool, and hence degrade the long-term regenerative competence of the adult white matter.
Glia 08/2008; 56(9):954-62. · 4.82 Impact Factor
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ABSTRACT: The statins have been proposed as possible therapeutic agents for a variety of autoimmune disorders, including multiple sclerosis. In a genomic screen, we found that glial progenitor cells (GPCs) of the adult human white matter expressed significant levels of the principal statin target, HMG-CoA reductase, as well as additional downstream members of the sterol synthesis pathway. We therefore asked if statin treatment might influence the differentiated fate of adult glial progenitor cells. To assess the functional importance of the sterol synthesis pathway to adult human glial progenitors, we used simvastatin or pravastatin to inhibit HMG-CoA reductase, and then assessed the phenotypic differentiation of the progenitors, as well as the molecular concomitants thereof. We found that both statins induced a dose-dependent induction of oligodendrocyte phenotype, and concomitant reduction in progenitor number. Oligodendrocyte commitment was associated with induction of the sterol-regulated nuclear co-receptor PPAR, and could be blocked by the specific PPAR antagonist GW9662. Thus, statins may promote oligodendrocyte lineage commitment by parenchymal glial progenitor cells; this might reduce the available progenitor pool, and hence degrade the long-term regenerative competence of the adult white matter. © 2008 Wiley-Liss, Inc.
Glia 06/2008; 56(9):954 - 962. · 4.82 Impact Factor
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Martha S Windrem,
Steven J Schanz,
Min Guo,
Guo-Feng Tian,
Vaughn Washco,
Nancy Stanwood,
Matthew Rasband, Neeta S Roy,
Maiken Nedergaard,
Leif A Havton,
Su Wang,
Steven A Goldman
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ABSTRACT: Congenitally hypomyelinated shiverer mice fail to generate compact myelin and die by 18-21 weeks of age. Using multifocal anterior and posterior fossa delivery of sorted fetal human glial progenitor cells into neonatal shiverer x rag2(-/-) mice, we achieved whole neuraxis myelination of the engrafted hosts, which in a significant fraction of cases rescued this otherwise lethal phenotype. The transplanted mice exhibited greatly prolonged survival with progressive resolution of their neurological deficits. Substantial myelination in multiple regions was accompanied by the acquisition of normal nodes of Ranvier and transcallosal conduction velocities, ultrastructurally normal and complete myelination of most axons, and a restoration of a substantially normal neurological phenotype. Notably, the resultant mice were cerebral chimeras, with murine gray matter but a predominantly human white matter glial composition. These data demonstrate that the neonatal transplantation of human glial progenitor cells can effectively treat disorders of congenital and perinatal hypomyelination.
Cell stem cell 06/2008; 2(6):553-65. · 23.56 Impact Factor
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ABSTRACT: Many common neurosurgical procedures, including anterior temporal lobectomy and endoscopic ventricular puncture, allow neurosurgeons to retrieve portions of the germinal subventricular zone (SVZ). Isolation and maintenance of precursor cells from this zone can be used for hypothesis-driven experiments with a goal of improving our understanding of the basic mechanisms of central nervous system injury or disease and the potential of cell-based therapies to treat them. This article details our ability to reliably harvest, isolate, characterize, and maintain normal adult human brain SVZ precursor cells.
Normal SVZ specimens were retrieved as part of anterior temporal lobe resections during planned epilepsy surgery. Dissociated SVZ specimens were plated and incubated in epidermal growth factor and basic fibroblast growth factor for more than 1 year to select for and expand normal neural precursor cells.
Self-renewal and immunocytochemical experiments proved the feasibility of long-term expansion of a slowly dividing nestin+, vimentin+, and glial fibrillary acidic protein-positive astrocyte capable of generating new neurons and glia. These mitotically active bipotent human precursors generated a large number of progeny and possessed significant self-renewal capacity, demonstrated by their ability to generate neurospheres. Cryopreservation was reliable with no loss of the precursor phenotype.
We have adapted techniques to allow for the isolation and long-term propagation of human adult neural precursors that are capable of generating both neurons and astrocytes in vitro. We have exploited the cell's self-renewal capacity to significantly and consistently expand human neural precursor cells for as long as 20 months. These findings suggest that cells derived from the SVZ during routine surgery may provide a renewable source of human neural precursor cells to study the biological mechanism of central nervous system disease or for application in cell-based human transplantation paradigms.
Neurosurgery 02/2008; 62(1):223-9; discussion 229-31. · 2.79 Impact Factor
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Nature Medicine 03/2007; 13(2):118-9. · 22.46 Impact Factor
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ABSTRACT: Traditional methods of generating immortalized lines of both somatic cells and their progenitors have relied on the use of oncogenes. However, the resulting lines are typically anaplastic in vitro and tumorigenic in vivo, and hence of limited utility. The overexpression of telomerase, as mediated by the induced overexpression of human telomerase reverse transcriptase (hTERT), has permitted the generation of stable, non-oncogenic lines of a variety of cell types. This strategy for immortalization has found special utility in the central nervous system, as few stable lines are available for the study of either human neural progenitor cells, or of neurons or glia of restricted phenotype. We describe the use of retroviral hTERT overexpression for generating lines of immortalized human neural progenitor cells, whose neuronal progeny are phenotypically restricted, post-mitotic and functionally competent. Although we focus here on telomerase immortalization of spinal neural progenitors, this is a broadly applicable protocol for using hTERT to immortalize human fetal neural progenitors of any pre-selected phenotype and for characterizing the cell lines thereby generated.
Nature Protocol 02/2007; 2(11):2815-25. · 8.36 Impact Factor
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ABSTRACT: Central neurocytoma (CN) is a rare periventricular tumor, whose derivation, lineage potential, and molecular regulation have been mostly unexplored. We noted that CN cells exhibited an antigenic profile typical of neuronal progenitor cells in vivo, yet in vitro generated neurospheres, divided in response to bFGF (basic fibroblast growth factor), activated the neuroepithelial enhancer of the nestin gene, and gave rise to both neuron-like cells and astrocytes. When CN gene expression was compared with that of both normal adult VZ (ventricular zone) and E/nestin:GFP (green fluorescent protein)-sorted native neuronal progenitors, significant overlap was noted. Marker analysis suggested that the gene expression pattern of CN was that of a proneuronal population; glial markers were conspicuously absent, suggesting that the emergence of astroglia from CN occurred only with passage. The expression pattern of CN was distinguished from that of native progenitor cells by a cohort of differentially expressed genes potentially involved in both the oncogenesis and phenotypic restriction of neurocytoma. These included both IGF2 and several components of its signaling pathway, whose sharp overexpression implicated dysregulated autocrine IGF2 signaling in CN oncogenesis. Both receptors and effectors of canonical wnt signaling, as well as GDF8 (growth differentiation factor 8), PDGF-D, and neuregulin, were differentially overexpressed by CN, suggesting that CN is characterized by the concurrent overactivation of these pathways, which may serve to drive neurocytoma expansion while restricting tumor progenitor phenotype. This strategy of comparing the gene expression of tumor cells to that of the purified native progenitors from which they derive may provide a focused approach to identifying transcripts important to stem and progenitor cell oncogenesis.
Journal of Neuroscience 12/2006; 26(48):12544-55. · 7.11 Impact Factor
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ABSTRACT: To direct human embryonic stem (HES) cells to a dopaminergic neuronal fate, we cocultured HES cells that were exposed to both sonic hedgehog and fibroblast growth factor 8 with telomerase-immortalized human fetal midbrain astrocytes. These astrocytes substantially potentiated dopaminergic neurogenesis by both WA09 and WA01 HES cells, biasing them to the A9 nigrostriatal phenotype. When transplanted into the neostriata of 6-hydroxydopamine-lesioned parkinsonian rats, the dopaminergic implants yielded a significant, substantial and long-lasting restitution of motor function. However, although rich in donor-derived tyrosine hydroxylase-expressing neurons, the grafts exhibited expanding cores of undifferentiated mitotic neuroepithelial cells, which can be tumorigenic. These results show the utility of recreating the cellular environment of the developing human midbrain while driving dopaminergic neurogenesis from HES cells, and they demonstrate the potential of the resultant cells to mediate substantial functional recovery in a model of Parkinson disease. Yet these data also mandate caution in the clinical application of HES cell-derived grafts, given their potential for phenotypic instability and undifferentiated expansion.
Nature Medicine 12/2006; 12(11):1259-68. · 22.46 Impact Factor
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Fraser J Sim,
Jennifer K Lang,
Ben Waldau, Neeta S Roy,
Theodore E Schwartz,
Webster H Pilcher,
Karen J Chandross,
Sridaran Natesan,
Jean E Merrill,
Steven A Goldman,
Steven A Goldmanm
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ABSTRACT: Glial progenitor cells are abundant in adult human white matter. This study was designed to identify signaling pathways regulating their self-renewal and fate.
We compared the transcriptional profiles of freshly sorted adult human white matter progenitor cells (WMPCs), purified by A2B5-based immunomagnetic sorting, with those of the white matter from which they derived.
We identified 132 genes differentially expressed by WMPCs; these included principal components of five receptor-defined signaling pathways, represented by platelet derived growth factor receptor alpha (PDGFRA) and type 3 fibroblast growth factor receptor (FGFR3), receptor tyrosine phosphatase-beta/zeta (RTPZ), notch, and syndecan3. WMPCs also differentially expressed the bone morphogenetic protein 4 (BMP4) inhibitors neuralin and BAMBI (BMP and activin membrane-bound inhibitor), suggesting tonic defense against BMP signaling. Differential overexpression of RTPZ was accompanied by that of its modulators pleiotrophin, NrCAM, tenascin, and the chondroitin sulfate proteoglycans, suggesting the importance of RTPZ signaling to WMPCs. When exposed to the RTPZ inhibitor bpV(phen), or lentiviral-shRNAi against RTPZ, WMPCs differentiated as oligodendrocytes. Conversely, when neuralin and BAMBI were antagonized by BMP4, astrocytic differentiation was induced, which was reversible by noggin.
The RTPZ and BMP pathways regulate the self-maintenance of adult human WMPCs, and can be modulated to induce their oligodendrocytic or astrocytic differentiation. As such, they provide targets by which to productively mobilize resident progenitor cells of the adult human brain.
Annals of Neurology 06/2006; 59(5):763-79. · 11.09 Impact Factor
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Fraser J. Sim PhD,
Jennifer K. Lang BS,
Ben Waldau MD,
Neeta S. Roy PhD,
Theodore E. Schwartz MD,
PhD Webster H. Pilcher MD,
Karen J. Chandross PhD,
Sridaran Natesan PhD,
Jean E. Merrill PhD,
PhD Steven A. Goldmanm MD,
Fraser J. Sim,
Jennifer K. Lang,
Ben Waldau, Neeta S. Roy,
Theodore E. Schwartz,
Webster H. Pilcher,
Karen J. Chandross,
Sridaran Natesan,
Jean E. Merrill,
Steven A. Goldmanm
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ABSTRACT: Objective
Glial progenitor cells are abundant in adult human white matter. This study was designed to identify signaling pathways regulating their self-renewal and fate.Methods
We compared the transcriptional profiles of freshly sorted adult human white matter progenitor cells (WMPCs), purified by A2B5-based immunomagnetic sorting, with those of the white matter from which they derived.ResultsWe identified 132 genes differentially expressed by WMPCs; these included principal components of five receptor-defined signaling pathways, represented by platelet derived growth factor receptor alpha (PDGFRA) and type 3 fibroblast growth factor receptor (FGFR3), receptor tyrosine phosphatase-β/ζ (RTPZ), notch, and syndecan3. WMPCs also differentially expressed the bone morphogenetic protein 4 (BMP4) inhibitors neuralin and BAMBI (BMP and activin membrane-bound inhibitor), suggesting tonic defense against BMP signaling. Differential overexpression of RTPZ was accompanied by that of its modulators pleiotrophin, NrCAM, tenascin, and the chondroitin sulfate proteoglycans, suggesting the importance of RTPZ signaling to WMPCs. When exposed to the RTPZ inhibitor bpV(phen), or lentiviral-shRNAi against RTPZ, WMPCs differentiated as oligodendrocytes. Conversely, when neuralin and BAMBI were antagonized by BMP4, astrocytic differentiation was induced, which was reversible by noggin.InterpretationThe RTPZ and BMP pathways regulate the self-maintenance of adult human WMPCs, and can be modulated to induce their oligodendrocytic or astrocytic differentiation. As such, they provide targets by which to productively mobilize resident progenitor cells of the adult human brain. Ann Neurol 2006;59:763–779
Annals of Neurology 04/2006; 59(5):763 - 779. · 11.09 Impact Factor
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Neeta S Roy,
Takahiro Nakano,
H Michael Keyoung,
Martha Windrem,
William K Rashbaum,
M Lita Alonso,
Jian Kang,
Weiguo Peng,
Melissa K Carpenter,
Jane Lin,
Maiken Nedergaard,
Steven A Goldman
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ABSTRACT: Lineage-restricted progenitors of the central nervous system (CNS) are not readily expandable because their mitotic competence is limited. Here we used retroviral overexpression of human telomerase reverse transcriptase (hTERT) to immortalize progenitors from human fetal spinal cord. The hTERT-immortalized cells divided in basic fibroblast growth factor (bFGF) expressed high telomerase activity, and gave rise to phenotypically restricted subpopulations of either glia or neurons. The latter included a prototypic line, hSC11V-TERT, that gave rise only to neurons. These included both chx10(+) interneurons and Islet1(+)/Hb9(+)/ChAT(+) motor neurons; the latter were recognized by green fluorescent protein (GFP) driven by the Hb9 enhancer. The neurons were postmitotic and achieved electrophysiologic competence. Upon xenograft to both fetal rat brain and injured adult spinal cord, they matured as neurons and survived for 6 months, with no evident tumorigenesis. The cells have survived >168 doublings in vitro, with karyotypic normalcy and without replicative senescence. hTERT overexpression thus permits the generation of progenitor lines able to give rise to phenotypically restricted neurons.
Nature Biotechnology 03/2004; 22(3):297-305. · 23.27 Impact Factor
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ABSTRACT: Both late-gestation and adult human forebrain contain large numbers of oligodendrocyte progenitor cells (OPCs). These cells may be identified by their A2B5(+)PSA-NCAM(-) phenotype (positive for the early oligodendrocyte marker A2B5 and negative for the polysialylated neural cell adhesion molecule). We used dual-color fluorescence-activated cell sorting (FACS) to extract OPCs from 21- to 23-week-old fetal human forebrain, and A2B5 selection to extract these cells from adult white matter. When xenografted to the forebrains of newborn shiverer mice, fetal OPCs dispersed throughout the white matter and developed into oligodendrocytes and astrocytes. By 12 weeks, the host brains showed extensive myelin production, compaction and axonal myelination. Isolates of OPCs derived from adult human white matter also myelinated shiverer mouse brain, but much more rapidly than their fetal counterparts, achieving widespread and dense myelin basic protein (MBP) expression by 4 weeks after grafting. Adult OPCs generated oligodendrocytes more efficiently than fetal OPCs, and ensheathed more host axons per donor cell than fetal cells. Both fetal and adult OPC phenotypes mediated the extensive and robust myelination of congenitally dysmyelinated host brain, although their differences suggested their use for different disease targets.
Nature Medicine 02/2004; 10(1):93-7. · 22.46 Impact Factor
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ABSTRACT: A distinct population of white matter progenitor cells (WMPCs), competent but not committed to generate oligodendrocytes, remains ubiquitous in the adult human subcortical white matter. These cells are present in both sexes and into senescence and may constitute as much as 4% of the cells of adult human capsular white matter. Transduction of adult human white matter dissociates with plasmids bearing early oligodendrocytic promoters driving fluorescent reporters permits the separation of these cells at high yield and purity, as does separation based on their expression of A2B5 immunoreactivity. Isolates of these cells survive xenograft to lysolecithin-demyelinated brain and migrate rapidly to infiltrate these lesions, without extending into normal white matter. Within several weeks, implanted progenitors mature as oligodendrocytes, and develop myelin-associated antigens. Lentiviral tagging with green fluorescent protein confirmed that A2B5-sorted progenitors develop myelin basic protein expression within regions of demyelination and that they fail to migrate when implanted into normal brain. Adult human white matter progenitor cells can thus disperse widely through regions of experimental demyelination and are able to differentiate as myelinating oligodendrocytes. This being the case, they may constitute appropriate vectors for cell-based remyelination strategies.
Journal of Neuroscience Research 10/2002; 69(6):966-75. · 2.74 Impact Factor
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ABSTRACT: We have examined primary human neuronal precursors (HNPs) from 18–22-week-old fetuses. We showed that E-NCAM/MAP2/β-III tubulin-immunoreactive neuronal precursors divide in vitro and could be induced to differentiate into mature neurons in 2 weeks. HNPs did not express nestin and differentiated slowly compared to rodent neuronal restricted precursors (NRPs, 5 days). Immunocytochemical and physiological analyses showed that HNPs could generate a heterogeneous population of neurons that expressed neurofilament-associated protein and various neurotransmitters, neurotransmitter synthesizing enzymes, voltage-gated ion channels, and ligand-gated neurotransmitter receptors and could fire action potentials. Undifferentiated and differentiated HNPs did not coexpress glial markers. Only a subset of cells that expressed GFP under the control of the Tα1 tubulin promoter was E-NCAM/β-III tubulin-immunoreactive, indicating nonexclusive overlap between these two HNP cell populations. Overall, HNPs resemble NRPs isolated from rodent tissue and appear to be a neuronal precursor population. J. Neurosci. Res. 66:356–368, 2001. © 2001 Wiley-Liss, Inc.
Journal of Neuroscience Research 10/2001; 66(3):356 - 368. · 2.74 Impact Factor
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ABSTRACT: Neural stem and precursor cells reside in the ventricular lining of the fetal forebrain, and may provide a cellular substrate for brain repair. To selectively identify and extract these cells, we infected dissociated fetal human brain cells with adenoviruses bearing the gene for green fluorescence protein (GFP), placed under the control of enhancer/promoters for two genes (nestin and musashi1) that are expressed in uncommitted neuroepithelial cells. The cells were then sorted by fluorescence-activated cell sorting (FACS) on the basis of E/nestin- or P/musashi1-driven GFP expression. Both P/musashi1:hGFP- and E/nestin:EGFP-sorted cells were multipotent: limiting dilution with clonal expansion as neurospheres, in tandem with retroviral lineage analysis and xenograft to E17 and P0-2 rat forebrain, revealed that each phenotype was able to both self-renew and co-generate neurons and glia. Thus, fluorescent genes placed under the control of early neural promoters allow neural stem cells to be specifically targeted, isolated, and substantially enriched from the fetal human brain.
Nature Biotechnology 08/2001; 19(9):843-850. · 23.27 Impact Factor
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ABSTRACT: Adult humans, like their nonhuman mammalian counterparts, harbor persistent neural progenitor cells in the forebrain ventricular lining. In the absence of adequate surface markers, however, these cells have proven difficult to isolate for study. We have previously identified and selected neural progenitor cells from both the fetal and adult rodent ventricular zone (VZ), by sorting forebrain cells transfected with plasmid DNA encoding the gene for green fluorescent protein driven by the early neuronal promoter for Tα1 tubulin (P/Tα1:hGFP). We have now extended this approach by purifying both P/Tα1:hGFP tubulin-defined neuronal progenitors, as well as potentially less committed E/nestin:hGFP-defined neural progenitor cells, from the adult human VZ. The ventricular wall of the temporal horn of the lateral ventricle was dissected from temporal lobes obtained from four adult patients undergoing therapeutic lobectomy. These samples were dissociated, and the cultured cells transduced with either P/Tα1:hGFP or E/nestin:EGFP plasmid DNA. A week later, the cells were redissociated, selected via fluorescence-activated cell sorting (FACS) on the basis of neural promoter-driven GFP expression, and replated. The majority of these cells expressed the early neuronal protein βIII-tubulin upon FACS; within the week thereafter, most matured as morphologically evident neurons that coexpressed βIII-tubulin and microtubule-associated protein (MAP)-2. Many of these neurons had incorporated bromodeoxyuridine in vitro in the days before FACS, indicating their mitogenesis in vitro. Thus, the use of fluorescent transgenes under the control of early neural promoters permits the enrichment of neuronal progenitor cells from the adult human ventricular zone. The specific acquisition, in both purity and number, of residual neural progenitor cells from the adult human brain may now permit hitherto unfeasible studies of both their biology and practical application. J. Neurosci. Res. 59:321–331, 2000 © 2000 Wiley-Liss, Inc.
Journal of Neuroscience Research 02/2000; 59(3):321 - 331. · 2.74 Impact Factor
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ABSTRACT: Neural precursor cells are dispersed widely throughout the adult brain. A population of multipotential progenitor cells, capable of giving rise to both neurons and glia, lines the cerebral ventricles of all adult animals, including humans. In addition, glial progenitor cells, which also have the capacity to generate multiple cell types, are dispersed throughout the subcortical white matter and cortex. Each of these categories of progenitor cells exists in, and has been isolated from, the adult human brain. We have begun to ask how these cells might be used therapeutically. We report here examples of two potential strategies for their use: (1) transplantation of phenotypically restricted progenitors, in which purified isolates of defined human precursor cells are implanted into disease sites, and (2) induction in vivo, in which resident progenitor cells are stimulated by delivered growth factors. We find that each of these strategies has potential therapeutic efficacy, and discuss the most likely and feasible clinical targets for their clinical application.
Clinical Neuroscience Research.
